Malaria is one of the leading causes of childhood mortality globally, responsible for the deaths of hundreds of thousands of children per year. While antimalarial drugs are widely available in endemic areas, their utility is compromised by the rapid development of drug resistance by Plasmodium falciparum parasites. All of the clinical symptoms of malaria are attributable to the stage of infection when parasites reside within erythrocytes. Since these cells are enucleated, they represent an attractive target for host-directed therapeutics, as they may be less likely to develop resistance. Population genetic studies support the idea that host factors can modulate the severity of malaria infections, but we have limited knowledge of the identity of such factors. We have designed an RNAi-based genetic screen to discover host factors required for invasion or growth of P. falciparum in erythrocytes. Our primary screen has identified ~10% of the erythrocyte proteome as candidates that may influence malaria pathogenesis. The overall goals of this proposal are to perform validation and functional studies on two of the most promising candidate host factors identified in the primary screen, as well as to perform secondary screens to validate and characterize the other candidates in a medium-throughput fashion. Along with the proposed research, the candidate's career development goals are to develop expertise in host-pathogen interactions in infectious diseases, molecular parasitology and erythrocyte genetics. These goals will be achieved by taking formal courses in Parasitology, Tropical Medicine, and Bioinformatics, as well as by attending Hematology and Parasitology seminars and conferences. She will receive direct mentorship from senior scientists in Parasitology, and will develop expertise in erythrocyte biology and genetics by collaborating with experts in the Hematology and functional genomics fields. In addition, the candidate will benefit from interactions with her Scientific Advisory Committee, which is composed of established scientists and physician-scientists from several disciplines, including Parasitology, Hematology, and Microbiology. The candidate's long-term career goals are to obtain a faculty position in academic medical department of Pediatric Infectious Diseases and to secure independent funding in order to continue her research on the host-pathogen interactions in malaria. The Harvard School of Public Health, Boston Children's Hospital, and The Broad Institute offer a rich training environment with all of the resources necessary to complete the proposed research. Boston Children's Hospital is committed to the candidate's career development plan and have assured that the candidate will have more than 80% protected time for the proposed research during the award period. PROJECT NARRATIVE: Plasmodium falciparum malaria is a significant cause of morbidity and mortality among children globally, responsible for over 600,000 deaths per year. Drug resistance hampers the effectiveness of parasite-directed antimalarial drugs currently in clinical use; an alternative approach is to target host proteins essential for malaria infection. Here, host proteins required for P. falciparum replication in erythrocytes will be identified using a genetic screen and characterized in terms of their roles in the host-parasite interaction. The results of this work will ultimately guide the rational development of host-targeted therapeutics for malaria.